WO2021056850A1 - 阿哌沙班与羧酸形成的共晶及其制备方法 - Google Patents

阿哌沙班与羧酸形成的共晶及其制备方法 Download PDF

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WO2021056850A1
WO2021056850A1 PCT/CN2019/125115 CN2019125115W WO2021056850A1 WO 2021056850 A1 WO2021056850 A1 WO 2021056850A1 CN 2019125115 W CN2019125115 W CN 2019125115W WO 2021056850 A1 WO2021056850 A1 WO 2021056850A1
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apixaban
crystal form
crystal
ray powder
powder diffraction
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French (fr)
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朱国荣
柯春龙
王臻
屠勇军
张鹏
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Zhejiang Tianyu Pharmaceutical Co Ltd
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Zhejiang Tianyu Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/08—Malonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to apixaban/carboxylic acid co-crystal and a preparation method thereof.
  • Apixaban its English name is Apixaban (trade name: Eliquis), and its chemical name is 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6 -[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, CAS:503612-47-3, its chemical structural formula as follows:
  • Apixaban is a new generation of antithrombotic drugs. It is a new type of direct inhibitor of factor Xa jointly developed by Bristol-Myers Squibb and Pfizer. The product is currently clinically used to prevent elective hip or knee replacements. Venous Thromboembolism (VTE) in adult patients.
  • VTE Venous Thromboembolism
  • Apixaban is almost insoluble in water, and has the disadvantages of slow dissolution rate and unfavorable absorption of drugs in the body. There is an urgent need to find a way to improve the dissolution rate of Apixaban.
  • patents CN101065379, US20070203178 and CN104086544 provide a variety of crystal forms of apixaban including hydrates and solvates. However, these crystal forms have no effect on the dissolution of apixaban. Not obvious.
  • Patent CN106986868 discloses co-crystals formed by apixaban with oxalic acid, isonicotine, 3-aminopyridine, and urea. These co-crystals have improved the dissolution rate of apixaban.
  • the co-crystals disclosed in this patent are medium and small Molecular isonicotine, 3-aminopyridine, urea and other bases have certain side effects on the human body.
  • 3-aminopyridine is a potential genotoxic impurity.
  • the purpose of the present invention is to overcome the shortcomings of the prior art and develop a new type of apixaban/carboxylic acid co-crystal with a specific molecular ratio and a preparation method thereof, which can improve the dissolution of apixaban while satisfying safe medication. Solve the shortcomings of slow dissolution rate and low dissolution rate of Apixaban, and improve its bioavailability.
  • the present invention provides a co-crystal formed by apixaban and carboxylic acid, wherein the molar ratio of apixaban to carboxylic acid is 1:0.5.
  • the carboxylic acid is malonic acid, D-malic acid, maleic acid, L-proline or L-tartaric acid, that is, these five
  • the co-crystals are apixaban/malonic acid co-crystal, apixaban/D-malic acid co-crystal, apixaban/maleic acid co-crystal, apixaban/L-proline co-crystal , Apixaban/L-tartaric acid eutectic, correspondingly called crystal form I, crystal form II, crystal form III, crystal form IV and crystal form V.
  • the X-ray powder diffraction of the crystal form I has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 5.7° ⁇ 0.2°, 5.9° ⁇ 0.2°, 11.0° ⁇ 0.2°, 11.5° ⁇ 0.2 °, 11.9° ⁇ 0.2°, 21.0° ⁇ 0.2°, there are characteristic peaks.
  • the X-ray powder diffraction of the crystal form I has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 5.7° ⁇ 0.2°, 5.9° ⁇ 0.2°, 7.1° ⁇ 0.2°, 11.0° ⁇ 0.2°, 11.5 ° ⁇ 0.2°, 11.9° ⁇ 0.2°, 15.5° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.0° ⁇ 0.2°, 17.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.4° ⁇ 0.2° are characteristic peak.
  • the X-ray powder diffraction of the crystal form I has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 5.7° ⁇ 0.2°, 5.9° ⁇ 0.2°, 7.1° ⁇ 0.2°, 11.0° ⁇ 0.2°, 11.5° ⁇ 0.2°, 11.9° ⁇ 0.2°, 13.3° ⁇ 0.2°, 13.5° ⁇ 0.2°, 15.5° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.0° ⁇ 0.2°, 17.4° ⁇ 0.2°, 19.1°
  • Fig. 1 X-ray powder diffraction pattern of the crystal form I is shown in Fig. 1.
  • the crystal form I loses 10.80% of its weight at 160°C (losing malonic acid molecules). According to the theoretical calculation, the molar ratio of apixaban to malonic acid is 1:0.5, and its thermogravimetric analysis (TGA) The map is shown in Figure 2.
  • the crystalline form I shows two endothermic peaks at about 160.2° C. and 238.7° C., and its differential scanning calorimetry (DSC) spectrum is shown in Fig. 3.
  • the crystalline form I is a powder with good appearance and fluidity, and the dissolution rate is 1.4 times that of apixaban, which is suitable for preparation into its oral preparation.
  • the X-ray powder diffraction of the crystal form II has diffraction angles 2 ⁇ of 5.7° ⁇ 0.2°, 8.7° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.2° ⁇ 0.2°, 17.6° ⁇ 0.2 °, 20.1° ⁇ 0.2°, 21.8° ⁇ 0.2°, there are characteristic peaks.
  • the X-ray powder diffraction of the crystal form II has a diffraction angle 2 ⁇ of 5.7° ⁇ 0.2°, 8.7° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.2° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.0 There are characteristic peaks at ° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.8° ⁇ 0.2°, 23.1° ⁇ 0.2°, 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form II has diffraction angles 2 ⁇ of 5.7° ⁇ 0.2°, 8.7° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.2° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.8° ⁇ 0.2°, 23.1° ⁇ 0.2°, 25.1° There are characteristic peaks at ⁇ 0.2°, 25.8° ⁇ 0.2°.
  • the crystal form II loses 12.01% of its weight (losing D-malic acid molecules) at 241°C. According to the theoretical calculation, the molar ratio of apixaban to D-malic acid is 1:0.5, and its TGA chart is shown in the figure 5.
  • the crystal form II has an endothermic peak at about 216.8° C., and its DSC chart is shown in Fig. 6.
  • the crystal form II is a powder with good appearance and fluidity, and the dissolution rate is 1.44 times that of apixaban, which is suitable for preparation into its oral preparation.
  • the X-ray powder diffraction of the crystal form III at the diffraction angle 2 ⁇ is 5.5° ⁇ 0.2°, 5.7° ⁇ 0.2°, 6.0° ⁇ 0.2°, 7.2° ⁇ 0.2°, 11.5° ⁇ 0.2 °, 15.8° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, there are characteristic peaks.
  • the X-ray powder diffraction of the crystal form III has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 5.7° ⁇ 0.2°, 6.0° ⁇ 0.2°, 7.2° ⁇ 0.2°, 11.5° ⁇ 0.2°, 11.9 ° ⁇ 0.2°, 13.3° ⁇ 0.2°, 13.5° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.9° ⁇ 0.2°, 20.3° ⁇ There are characteristic peaks at 0.2°, 21.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form III has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 5.7° ⁇ 0.2°, 6.0° ⁇ 0.2°, 7.2° ⁇ 0.2°, 11.5° ⁇ 0.2°, 11.9° ⁇ 0.2°, 13.3° ⁇ 0.2°, 13.5° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.9° ⁇ 0.2°, 20.3°
  • the crystal form III loses 10.40% of its weight at 161° C. (loss of maleic acid molecule). According to the theoretical calculation, the molar ratio of apixaban to maleic acid is 1:0.5, and its TGA chart is shown in Figure 8.
  • the crystal form III has endothermic peaks at about 155.3°C, 180.1°C, and 238.6°C, and its DSC chart is shown in Fig. 9.
  • the crystal form III is a powder with good appearance and fluidity, and the dissolution rate is 1.53 times that of apixaban, which is suitable for preparing into its oral preparation.
  • the X-ray powder diffraction of the crystal form IV at the diffraction angle 2 ⁇ is 5.5° ⁇ 0.2°, 5.7° ⁇ 0.2°, 5.9° ⁇ 0.2°, 7.0° ⁇ 0.2°, 11.9° ⁇ 0.2 °, 17.4° ⁇ 0.2°, 19.0° ⁇ 0.2°, 21.0° ⁇ 0.2°, there are characteristic peaks.
  • the X-ray powder diffraction of the crystal form IV has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 5.7° ⁇ 0.2°, 5.9° ⁇ 0.2°, 7.0° ⁇ 0.2°, 11.0° ⁇ 0.2°, 11.9 ° ⁇ 0.2°, 13.5° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.0° ⁇ 0.2°, 21.0° ⁇ 0.2° are characteristic peak.
  • the X-ray powder diffraction of the crystal form IV has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 5.7° ⁇ 0.2°, 5.9° ⁇ 0.2°, 7.0° ⁇ 0.2°, 11.0° ⁇ 0.2°, 11.9° ⁇ 0.2°, 13.5° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.0° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.5° There are characteristic peaks at ⁇ 0.2°, 22.5° ⁇ 0.2°, 24.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form IV is shown in FIG. 10.
  • the crystal form IV loses 10.50% of its weight at 158°C (losing the L-proline molecule). According to the theoretical calculation, the molar ratio of apixaban to L-proline is 1:0.5, and its TGA profile See Figure 11.
  • the crystalline form IV has endothermic peaks at about 159.1°C and 237.0°C, and its DSC chart is shown in Figure 12.
  • the crystalline form IV is a powder with good appearance and fluidity, and the dissolution rate is 1.54 times that of apixaban, which is suitable for preparation into its oral preparation.
  • the X-ray powder diffraction of the crystal form V has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, 11.0° ⁇ 0.2°, 17.9° ⁇ 0.2 °, 19.1° ⁇ 0.2°, 22.7° ⁇ 0.2°, there are characteristic peaks.
  • the X-ray powder diffraction of the crystal form V has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, 11.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.8 ° ⁇ 0.2°, 16.0° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.5° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.7° ⁇ There is a characteristic peak at 0.2°.
  • the X-ray powder diffraction of the crystal form V has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.0° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.5° ⁇ 0.2°, 21.2° There are characteristic peaks at ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.7° ⁇ 0.2°, 24.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form V is shown in FIG. 13.
  • the crystal form V loses 12.13% of its weight (losing L-tartaric acid molecules) at 161.8°C. According to the theoretical calculation, the molar ratio of apixaban to L-tartaric acid is 1:0.5, and its TGA chart is shown in Figure 14.
  • the crystalline form V has endothermic peaks at about 165.7°C, 215.7°C, and 234.0°C, and its DSC chart is shown in Fig. 15.
  • the crystal form V is a powder with good appearance and fluidity, and the dissolution rate is 1.45 times that of apixaban, which is suitable for preparing into its oral preparation.
  • the present invention also provides a method for preparing the above five types of co-crystals, and the method includes:
  • the carboxylic acid and apixaban are dissolved in a mixed solvent of trifluoroethanol and a poor solvent, stirred for crystallization, filtered, and dried to obtain apixaban/carboxylic acid co-crystal.
  • the co-crystal preparation method of the present invention includes:
  • the molar ratio of apixaban to carboxylic acid used is 1:0.5-1.1, preferably 1:0.7-1.
  • the weight-to-volume ratio (g/mL) of apixaban to trifluoroethanol is 1:5-6.
  • the weight-volume ratio (g/mL) of apixaban to the poor solvent used is 1:2.5-3.0.
  • the poor solvent used is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, preferably methanol.
  • the carboxylic acid used is selected from malonic acid, D-malic acid, maleic acid, L-proline or L-tartaric acid.
  • Figure 1 is an X-ray powder diffraction pattern of apixaban/malonic acid co-crystal form I;
  • Figure 2 is the TGA spectrum of apixaban/malonic acid co-crystal form I
  • Figure 3 is a DSC spectrum of apixaban/malonic acid co-crystal form I
  • Figure 4 is an X-ray powder diffraction pattern of apixaban/D-malic acid co-crystal form II;
  • Figure 5 is the TGA spectrum of Apixaban/D-malic acid co-crystal form II
  • Figure 6 is a DSC chart of Apixaban/D-malic acid co-crystal form II
  • Figure 7 is an X-ray powder diffraction pattern of apixaban/maleic acid co-crystal form III
  • Figure 8 is the TGA spectrum of apixaban/maleic acid co-crystal form III
  • Figure 9 is a DSC chart of apixaban/maleic acid co-crystal form III
  • Figure 10 is an X-ray powder diffraction pattern of apixaban/L-proline co-crystal form IV;
  • Figure 11 is the TGA spectrum of apixaban/L-proline co-crystal form IV;
  • Figure 12 is a DSC chart of apixaban/L-proline co-crystal form IV;
  • Figure 13 is an X-ray powder diffraction pattern of apixaban/L-tartaric acid co-crystal form V;
  • Figure 14 is the TGA spectrum of apixaban/L-tartaric acid co-crystal form V;
  • Figure 15 is a DSC chart of apixaban/L-tartaric acid co-crystal form V;
  • Figures 16A to 16F are respectively the dissolution profiles of apixaban N-1 crystal form and five apixaban/carboxylic acid co-crystals of the present invention.
  • X-ray powder diffraction pattern was obtained with PANalytical "X'pert Powder” powder X-ray diffractometer, copper palladium, incident wavelength: 1.54 angstroms;
  • the differential scanning calorimetry atlas was obtained with a METTLER TOLEDO differential scanning calorimeter, the sample loading amount was 5.00mg, and the heating rate was 10.00K/min;
  • thermogravimetric analysis chart collects TGA data on TA Instruments Q500.
  • the abscissa represents the temperature (°C)
  • the ordinate represents the percentage of weight loss (%).
  • the obtained co-crystal is apixaban/malonic acid co-crystal form I.
  • the X-ray powder diffraction data of the sample is shown in Figure 1 and Table 1; the TGA spectrum is shown in Figure 2; and the DSC spectrum is shown in Figure 3.
  • the obtained co-crystal is apixaban/D-malic acid co-crystal form II.
  • the X-ray powder diffraction data of the sample is shown in Figure 4 and Table 2; the TGA spectrum is shown in Figure 5; and the DSC spectrum is shown in Figure 6.
  • the obtained co-crystal is apixaban/maleic acid co-crystal form III.
  • the X-ray powder diffraction data of the sample is shown in Figure 7 and Table 3; the TGA spectrum is shown in Figure 8; and the DSC spectrum is shown in Figure 9.
  • the obtained co-crystal is apixaban/L-proline co-crystal form IV.
  • the X-ray powder diffraction data of the sample is shown in Fig. 10 and Table 4; the TGA pattern is shown in Fig. 11; and the DSC pattern is shown in Fig. 12.
  • the obtained co-crystal is apixaban/L-tartaric acid co-crystal form V.
  • the X-ray powder diffraction data of the sample is shown in Figure 13 and Table 5; the TGA spectrum is shown in Figure 14; and the DSC spectrum is shown in Figure 15.
  • Test Example 1 Dissolution test of apixaban/carboxylic acid co-crystal
  • hydrochloric acid solution Take 9ml of hydrochloric acid into 1000ml of water and stir evenly.

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Abstract

提供了阿哌沙班与羧酸形成的共晶及其制备方法，所述共晶包括阿哌沙班/丙二酸共晶、阿哌沙班/D‑苹果酸共晶、阿哌沙班/马来酸共晶、阿哌沙班/L‑脯氨酸共晶、阿哌沙班/L‑酒石酸共晶。所述共晶解决了阿哌沙班溶解速度慢、溶出度低的缺点，具有改善的阿哌沙班溶出度，有利于提高生物利用度。

Description

阿哌沙班与羧酸形成的共晶及其制备方法 技术领域
本发明涉及药物化学领域，特别涉及阿哌沙班/羧酸共晶及其制备方法。
背景技术
阿哌沙班，其英文名称为Apixaban(商品名：Eliquis)，其化学名称为4,5,6,7-四氢-1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代-1-哌啶基)苯基]-1H-吡唑并[3,4-c]吡啶-3-甲酰胺，CAS：503612-47-3，其化学结构式如下：
Figure PCTCN2019125115-appb-000001
阿哌沙班是新一代的抗血栓药物，它是由美国百时美-施贵宝和辉瑞公司联合开发的新型Xa因子直接抑制剂，目前该产品临床用于预防择期髋关节或膝关节置换术的成年患者出现的静脉血栓栓塞症(VTE)。
阿哌沙班几乎不溶于水，存在溶解速度慢，不利于体内药物的吸收等缺点。急需寻求提高阿哌沙班溶出度的方法。为解决这一问题，专利CN101065379、US20070203178及CN104086544等提供了阿哌沙班的包括水合物和溶剂合物在内的多种晶型，然而这些晶型对于阿哌沙班溶出度的改善效果并不明显。
专利CN106986868公开了阿哌沙班与草酸、异烟碱、3-氨基吡啶、尿素形成的共晶体，这些共晶体对阿哌沙班的溶出度有所提高，然而，该专利公开的共晶体中小分子异烟碱、3-氨基吡啶、尿素等碱对人体有一定的副作用，比如3-氨基吡啶是潜在的基因毒性杂质。这些不利因素不利于将上述共晶体开发为对人体安全的口服制剂。
发明内容
本发明的目的在于克服现有技术不足，开发新型的具有特定分子配比的阿哌沙班/羧酸共晶及其制备方法，在满足安全用药的同时，改善阿哌沙班的溶出度，解决阿哌沙班溶解速度慢、溶出度低的缺点，提高其生物利用度。
本发明提供了阿哌沙班与羧酸形成的共晶，其中所述阿哌沙班与羧酸的摩尔比为1:0.5。
在本发明的阿哌沙班与羧酸形成的共晶中，所述羧酸为丙二酸、D-苹果酸、马来酸、L-脯氨酸或L-酒石酸，即，这五种共晶分别为阿哌沙班/丙二酸共晶，阿哌沙班/D-苹果酸共晶、阿哌沙班/马来酸共晶，阿哌沙班/L-脯氨酸共晶，阿哌沙班/L-酒石酸共晶，对应称 为晶型I、晶型II、晶型III、晶型IV及晶型V。
在本发明的阿哌沙班与羧酸形成的共晶中，阿哌沙班/丙二酸共晶晶型I的结构式如下式1所示:
Figure PCTCN2019125115-appb-000002
所述晶型I具有如下特性：
使用Cu-Kα辐射，所述晶型I的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，11.0°±0.2°，11.5°±0.2°，11.9°±0.2°，21.0°±0.2°的位置有特征峰。
进一步地，所述晶型I的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.1°±0.2°，11.0°±0.2°，11.5°±0.2°，11.9°±0.2°，15.5°±0.2°，15.7°±0.2°，16.0°±0.2°，17.4°±0.2°，21.0°±0.2°，21.4°±0.2°的位置有特征峰。
更进一步地，所述晶型I的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.1°±0.2°，11.0°±0.2°，11.5°±0.2°，11.9°±0.2°，13.3°±0.2°，13.5°±0.2°，15.5°±0.2°，15.7°±0.2°，16.0°±0.2°，17.4°±0.2°，19.1°±0.2°，20.2°±0.2°，21.0°±0.2°，21.4°±0.2°，21.8°±0.2°，22.4°±0.2°，24.1°±0.2°的位置有特征峰。
非限制地，所述晶型I的X-射线粉末衍射图见图1。
非限制地，所述晶型I在160℃处失重10.80％(失去丙二酸分子)，按理论计算阿哌沙班与丙二酸的摩尔比为1:0.5，其热重分析(TGA)图谱见图2。
非限制地，所述晶型I在约160.2℃和238.7℃处显示有两个吸热峰，其差式扫描量热(DSC)图谱见图3。
所述晶型I为具有良好外观和流动性的粉末，溶出度为阿哌沙班的1.4倍，适于制备成其口服制剂。
在本发明的阿哌沙班与羧酸形成的共晶中，阿哌沙班/D-苹果酸共晶晶型II的结构式如下式2所示:
Figure PCTCN2019125115-appb-000003
所述晶型II具有如下特性：
使用Cu-Kα辐射，所述晶型II的X-射线粉末衍射在衍射角2θ为5.7°±0.2°，8.7°±0.2°，11.5°±0.2°，13.2°±0.2°，17.6°±0.2°，20.1°±0.2°，21.8°±0.2°的位置有特征峰。
进一步地，所述晶型II的X-射线粉末衍射在衍射角2θ为5.7°±0.2°，8.7°±0.2°，11.5°±0.2°，13.2°±0.2°，15.8°±0.2°，16.0°±0.2°，17.6°±0.2°，18.5°±0.2°，20.1°±0.2°，21.8°±0.2°，23.1°±0.2°，25.1°±0.2°的位置有特征峰。
更进一步地，所述晶型II的X-射线粉末衍射在衍射角2θ为5.7°±0.2°，8.7°±0.2°，11.5°±0.2°，13.2°±0.2°，15.8°±0.2°，16.0°±0.2°，16.2°±0.2°，16.5°±0.2°，17.6°±0.2°，18.5°±0.2°，20.1°±0.2°，21.8°±0.2°，23.1°±0.2°，25.1°±0.2°，25.8°±0.2°的位置有特征峰。
非限制地，所述晶型II的X-射线粉末衍射图见图4。
非限制地，所述晶型II在241℃处失重12.01％(失去D-苹果酸分子)，按理论推算阿哌沙班与D-苹果酸的摩尔比为1:0.5，其TGA图谱见图5。
非限制地，所述晶型II在约216.8℃处具有吸热峰，其DSC图谱见图6。
所述晶型II为具有良好外观和流动性的粉末，溶出度为阿哌沙班的1.44倍，适于制备成其口服制剂。
在本发明的阿哌沙班与羧酸形成的共晶中，阿哌沙班/马来酸共晶晶型III的结构式如下式3所示:
Figure PCTCN2019125115-appb-000004
所述晶型III具有如下特性：
使用Cu-Kα辐射，所述晶型III的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，6.0°±0.2°，7.2°±0.2°，11.5°±0.2°，15.8°±0.2°，16.1°±0.2°，17.4°±0.2°，21.0°±0.2°的位置有特征峰。
进一步地，所述晶型III的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，6.0°±0.2°，7.2°±0.2°，11.5°±0.2°，11.9°±0.2°，13.3°±0.2°，13.5°±0.2°，15.8°±0.2°，16.1°±0.2°，17.4°±0.2°，19.1°±0.2°，19.9°±0.2°，20.3°±0.2°，21.0°±0.2°的位置有特征峰。
更进一步地，所述晶型III的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，6.0°±0.2°，7.2°±0.2°，11.5°±0.2°，11.9°±0.2°，13.3°±0.2°，13.5°±0.2°，15.8°±0.2°，16.1°±0.2°，17.4°±0.2°，19.1°±0.2°，19.9°±0.2°，20.3°±0.2°，21.0°±0.2°，21.9°±0.2°，22.5°±0.2°，24.1°±0.2°的位置有特征峰。
非限制地，所述晶型III的X-射线粉末衍射图见图7。
非限制地，所述晶型III在161℃处失重10.40％(失去马来酸分子)，按理论推算阿哌沙班与马来酸的摩尔比为1:0.5，其TGA图谱见图8。
非限制地，所述晶型III在约155.3℃、180.1℃和238.6℃处具有吸热峰，其DSC图谱见图9。
所述晶型III为具有良好外观和流动性的粉末，溶出度为阿哌沙班的1.53倍，适于制备成其口服制剂。
在本发明的阿哌沙班与羧酸形成的共晶中，阿哌沙班/L-脯氨酸共晶晶型IV的结构式如下式4所示:
Figure PCTCN2019125115-appb-000005
所述晶型IV具有如下特性：
使用Cu-Kα辐射，所述晶型IV的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.0°±0.2°，11.9°±0.2°，17.4°±0.2°，19.0°±0.2°，21.0°±0.2°的位置有特征峰。
进一步地，所述晶型IV的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.0°±0.2°，11.0°±0.2°，11.9°±0.2°，13.5°±0.2°，15.5°±0.2°，16.1°±0.2°，17.4°±0.2°，17.8°±0.2°，19.0°±0.2°，21.0°±0.2°的位置有特征峰。
更进一步地，所述晶型IV的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.0°±0.2°，11.0°±0.2°，11.9°±0.2°，13.5°±0.2°，15.5°±0.2°，16.1°±0.2°，17.4°±0.2°，17.8°±0.2°，19.0°±0.2°，21.0°±0.2°，21.5°±0.2°，22.5°±0.2°，24.1°±0.2°的位置有特征峰。
非限制地，所述晶型IV的X-射线粉末衍射图见图10。
非限制地，所述晶型IV在158℃处失重10.50％(失去L-脯氨酸分子)，按理论推算阿哌沙班与L-脯氨酸的摩尔比为1:0.5，其TGA图谱见图11。
非限制地，所述晶型IV在约159.1℃和237.0℃处具有吸热峰，其DSC图谱见图12。
所述晶型IV为具有良好外观和流动性的粉末，溶出度为阿哌沙班的1.54倍，适于制备成其口服制剂。
在本发明的阿哌沙班与羧酸形成的共晶中，阿哌沙班/L-酒石酸共晶晶型V的结构式如下式5所示:
Figure PCTCN2019125115-appb-000006
所述晶型V具有如下特性：
使用Cu-Kα辐射，所述晶型V的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，7.1°±0.2°，8.6°±0.2°，11.0°±0.2°，17.9°±0.2°，19.1°±0.2°，22.7°±0.2°的位置有特征峰。
进一步地，所述晶型V的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，7.1°±0.2°，8.6°±0.2°，11.0°±0.2°，14.3°±0.2°，15.8°±0.2°，16.0°±0.2°，17.9°±0.2°，19.1°±0.2°，20.3°±0.2°，20.5°±0.2°，21.2°±0.2°，21.5°±0.2°，22.7°±0.2°的位置有特征峰。
更进一步地，所述晶型V的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，7.1°±0.2°，8.6°±0.2°，11.0°±0.2°，12.8°±0.2°，14.3°±0.2°，15.8°±0.2°，16.0°±0.2°，17.9°±0.2°，19.1°±0.2°，20.0°±0.2°，20.3°±0.2°，20.5°±0.2°，21.2°±0.2°，21.5°±0.2°，22.7°±0.2°，24.5°±0.2°的位置有特征峰。
非限制地，所述晶型V的X-射线粉末衍射图见图13。
非限制地，所述晶型V在161.8℃处失重12.13％(失去L-酒石酸分子)，按理论推算阿哌沙班与L-酒石酸的摩尔比为1:0.5，其TGA图谱见图14。
非限制地，所述晶型V在约165.7℃、215.7℃和234.0℃处具有吸热峰，其DSC图谱见图15。
所述晶型V为具有良好外观和流动性的粉末，溶出度为阿哌沙班的1.45倍，适于制备成其口服制剂。
上述五种阿哌沙班/羧酸共晶的溶出度曲线见图16B至图16F。结果表明五种共晶的溶出度都比阿哌沙班要高，其中阿哌沙班/脯氨酸共晶晶型IV溶出度最高，很快能达到阿哌沙班的2倍，之后渐渐下降。
本发明同时提供上述五种共晶的制备方法，该方法包括：
将羧酸与阿哌沙班溶于三氟乙醇与不良溶剂的混合溶剂中，搅拌析晶，过滤，干燥，获得阿哌沙班/羧酸共晶。
优选地，本发明的共晶制备方法包括：
将羧酸与阿哌沙班溶于三氟乙醇与不良溶剂的混合溶剂中，于30-35℃搅拌18小时，而后降温至0-5℃析晶2-10小时，将所得固体过滤，于55℃真空干燥后获得阿哌沙班/羧酸共晶。
在本发明的共晶制备方法中，所使用的阿哌沙班与羧酸的摩尔比为1:0.5-1.1，优选1:0.7-1。
在本发明的共晶制备方法中，所使用的阿哌沙班与三氟乙醇的重量体积比(g/mL)为1:5-6。
在本发明的共晶制备方法中，所使用的阿哌沙班与不良溶剂的重量体积比(g/mL)为1:2.5-3.0。
在本发明的共晶制备方法中，所使用的不良溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇，优选为甲醇。
在本发明的共晶制备方法中，所使用的羧酸选自丙二酸、D-苹果酸、马来酸、L-脯氨酸或L-酒石酸。
附图说明
图1是阿哌沙班/丙二酸共晶晶型I的X-射线粉末衍射图谱；
图2是阿哌沙班/丙二酸共晶晶型I的TGA图谱；
图3是阿哌沙班/丙二酸共晶晶型I的DSC图谱；
图4是阿哌沙班/D-苹果酸共晶晶型II的X-射线粉末衍射图谱；
图5是阿哌沙班/D-苹果酸共晶晶型II的TGA图谱；
图6是阿哌沙班/D-苹果酸共晶晶型II的DSC图谱；
图7是阿哌沙班/马来酸共晶晶型III的X-射线粉末衍射图谱；
图8是阿哌沙班/马来酸共晶晶型III的TGA图谱；
图9是阿哌沙班/马来酸共晶晶型III的DSC图谱；
图10是阿哌沙班/L-脯氨酸共晶晶型IV的X-射线粉末衍射图谱；
图11是阿哌沙班/L-脯氨酸共晶晶型IV的TGA图谱；
图12是阿哌沙班/L-脯氨酸共晶晶型IV的DSC图谱；
图13是阿哌沙班/L-酒石酸共晶晶型V的X-射线粉末衍射图谱；
图14是阿哌沙班/L-酒石酸共晶晶型V的TGA图谱；
图15是阿哌沙班/L-酒石酸共晶晶型V的DSC图谱；
图16A至图16F分别是阿哌沙班N-1晶型和本发明的五种阿哌沙班/羧酸共晶的溶出度曲线图。
具体实施方式
本发明实施例中使用的主要原料的信息如下:
Figure PCTCN2019125115-appb-000007
本发明所得的共晶采用如下仪器进行表征：
X-射线粉末衍射图谱采用帕纳科“X'pert Powder”粉末X射线衍射仪获得，铜钯，入射波长：1.54埃；
差示扫描量热图谱采用梅特勒-托利多差示扫描量热仪获得，样品装载量5.00mg，升温速率10.00K/min；
热重分析图谱在TA Instruments Q500上采集TGA数据。在TGA图中，横坐标表示温度(℃)，纵坐标表示失重的百分含量(％)。
实施例1：阿哌沙班/丙二酸共晶晶型I的制备
室温下，在反应瓶中加入丙二酸10.2g，阿哌沙班60g和三氟乙醇350ml、甲醇170mL，搅拌1小时溶解后，将所得溶液保温在30～35℃，继续搅拌18小时，而后控制降温速率10-15℃/小时，将结晶溶液降温至0～5℃析晶，析晶5小时，有大量晶体析出，将所得晶体过滤并用少量甲醇洗涤，然后在55℃真空干燥24小时得53.5g阿哌沙班/丙二酸共晶。经检测，所得共晶为阿哌沙班/丙二酸共晶晶型I。样品的X-射线粉末衍射数据如图1和表1所示；TGA图谱如图2所示；DSC图谱如图3所示。
表1
2θ(°) 相对强度(％)
5.5 64
5.7 100
5.9 60
7.1 12
11.0 20
11.5 37
11.9 21
13.3 14
13.5 13
15.5 22
15.7 34
16.0 35
17.4 35
19.1 23
19.7 19.4
20.2 31
20.4 22
21.0 66
21.4 49
21.8 30
22.4 42
23.1 12
24.1 29
24.7 17
25.8 14
30.8 15
实施例2：阿哌沙班/D-苹果酸共晶晶型II的制备
室温下，在反应瓶中加入D-苹果酸13.2g，阿哌沙班60g和三氟乙醇350ml、甲醇170mL，搅拌1小时溶解后，将所得溶液保温在30～35℃，继续搅拌18小时，而后控制降温速率10-15℃/小时，将结晶溶液降温至0～5℃析晶，析晶6小时，有大量晶体析出，将所得晶体过滤并用少量甲醇洗涤，然后在55℃真空干燥24小时得48.6g阿哌沙班/D-苹果酸共晶。 经检测，所得共晶为阿哌沙班/D-苹果酸共晶晶型II。样品的X-射线粉末衍射数据如图4和表2所示；TGA图谱如图5所示；DSC图谱如图6所示。
表2
Figure PCTCN2019125115-appb-000008
实施例3：阿哌沙班/马来酸共晶晶型III的制备
室温下，在反应瓶中加入马来酸11.3g，阿哌沙班60g和三氟乙醇350ml、甲醇170mL，搅拌1小时溶解后，将所得溶液保温在30～35℃，继续搅拌18小时，而后控制降温速率10-15℃/小时，将结晶溶液降温至0～5℃析晶，析晶5小时，有大量晶体析出，将所得晶体过滤并用少量甲醇洗涤，然后在55℃真空干燥24小时得45.3g阿哌沙班/马来酸共晶。经检测，所得共晶为阿哌沙班/马来酸共晶晶型III。样品的X-射线粉末衍射数据如图7和表3所示；TGA图谱如图8所示；DSC图谱如图9所示。
表3
2θ(°) 相对强度(％)
5.5 64
5.7 100
6.0 60
7.2 11
11.5 37
11.9 21
13.3 14
13.5 12
15.5 22
15.8 34
16.1 35
16.6 5
17.4 35
19.1 23
19.9 19
20.3 31
21.0 66
21.9 30
22.5 41
23.2 12
24.1 29
24.9 17
25.8 14
实施例4：阿哌沙班/L-脯氨酸共晶晶型IV的制备
室温下，在反应瓶中加入L-脯氨酸11.3g，阿哌沙班60g和三氟乙醇350ml、甲醇170mL，搅拌1小时溶解后，将所得溶液保温在30～35℃，继续搅拌18小时，而后控制降温速率10-15℃/小时，将结晶溶液降温至0～5℃析晶，析晶6小时，有大量晶体析出，将所得晶体过滤并用少量甲醇洗涤，然后在55℃真空干燥24小时得54.3g阿哌沙班/L-脯氨酸共晶。经检测，所得共晶为阿哌沙班/L-脯氨酸共晶晶型IV。样品的X-射线粉末衍射数据如图10和表4所示；TGA图谱如图11所示；DSC图谱如图12所示。
表4
2θ(°) 相对强度(％)
5.5 43
5.7 40
5.9 100
7.0 10
11.0 18
11.5 10
11.9 28
13.5 20
15.5 18
16.1 20
17.4 40
17.8 15
19.0 28
20.2 13
20.4 13
21.0 43
21.5 25
21.8 11
22.5 33
22.7 15
24.1 16
25.8 11
30.8 16
实施例5：阿哌沙班/L-酒石酸共晶晶型V的制备
室温下，在反应瓶中加入L-酒石酸19.6g，阿哌沙班60g和三氟乙醇350ml、甲醇170mL，搅拌1小时溶解后，将所得溶液保温在30～35℃，继续搅拌18小时，而后控制降温速率10-15℃/小时，将结晶溶液降温至0～5℃析晶，析晶6小时，有大量晶体析出，将所得晶体过滤并用少量甲醇洗涤，然后在55℃真空干燥24小时得阿哌沙班/L-酒石酸共晶。经检测，所得共晶为阿哌沙班/L-酒石酸共晶晶型V。样品的X-射线粉末衍射数据如图13和表5所示；TGA图谱如图14所示；DSC图谱如图15所示。
表5
2θ(°) 相对强度(％)
5.5 100
5.7 12
7.1 19
8.6 12
10.6 10
11.0 64
11.4 16
12.8 12
14.3 18
15.8 22
16.0 23
17.9 30
19.1 35
19.9 13
20.0 18
20.3 36
20.5 46
21.2 40
21.5 44
22.7 87
24.5 22
24.7 14
25.1 18
25.2 15
27.8 15
31.4 18
试验例1：阿哌沙班/羧酸共晶的溶出度试验
按照现行中国药典的溶出度试验指导原则，设计溶出度实验，分别考察本发明制备的五种阿哌沙班/羧酸共晶的溶出度，具体方案如下：
取本发明的五种阿哌沙班/羧酸共晶及阿哌沙班N-1晶型(按照专利CN101065379A公开的方法制备得到)，在溶出介质(0.1mol/L的盐酸)中进行平衡溶解度的研究。
表6溶出设备和参数
Figure PCTCN2019125115-appb-000009
Figure PCTCN2019125115-appb-000010
表7物料及设备
阿哌沙班原料药
聚偏氟乙烯滤膜(PVDF)，0.45μm
磷酸二氢钾
氢氧化钠
磷酸
盐酸
溶出介质的配制
0.1mol/L盐酸溶液：取9ml盐酸至1000ml水中，搅匀。
溶解度饱和溶液的配制
溶出条件达到后，称取500mg样品粉末投入溶出杯中，开始转动，立刻计时，经1、2、3、4、6、8、10、12、14、16、18、20、22、24小时，用配有10μm高分子聚乙烯滤膜的取样针取样，通过0.45μm聚偏氟乙烯(PVDF)滤膜在线过滤，即得。
结果如图16A至图16F所示。由图16A至图16F可见，本发明的五种共晶的溶出度都比阿哌沙班N-1晶型要高，其中阿哌沙班/L-脯氨酸共晶晶型IV溶出度最高。
本发明的方法已经通过优选实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，从技术层面讲，对所述的实施步骤中若干优化也应视为本发明的保护范围。

Claims (21)

  1. 阿哌沙班与羧酸形成的共晶，其中所述阿哌沙班与羧酸的摩尔比为1:0.5。
  2. 如权利要求1所述的共晶，其中所述羧酸为丙二酸、D-苹果酸、马来酸、L-脯氨酸或L-酒石酸。
  3. 如权利要求1或2所述的共晶，其中所述阿哌沙班与丙二酸形成式1所示的共晶晶型I：
    Figure PCTCN2019125115-appb-100001
    使用Cu-Kα辐射，所述晶型I的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，11.0°±0.2°，11.5°±0.2°，11.9°±0.2°，21.0°±0.2°的位置有特征峰。
  4. 根据权利要求3所述的共晶，其中所述晶型I的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.1°±0.2°，11.0°±0.2°，11.5°±0.2°，11.9°±0.2°，15.5°±0.2°，15.7°±0.2°，16.0°±0.2°，17.4°±0.2°，21.0°±0.2°，21.4°±0.2°的位置有特征峰。
  5. 根据权利要求3所述的共晶，其中所述晶型I的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.1°±0.2°，11.0°±0.2°，11.5°±0.2°，11.9°±0.2°，13.3°±0.2°，13.5°±0.2°，15.5°±0.2°，15.7°±0.2°，16.0°±0.2°，17.4°±0.2°，19.1°±0.2°，20.2°±0.2°，21.0°±0.2°，21.4°±0.2°，21.8°±0.2°，22.4°±0.2°，24.1°±0.2°的位置有特征峰。
  6. 如权利要求1或2所述的共晶，其中所述阿哌沙班与D-苹果酸形成式2所示的共晶晶型II：
    Figure PCTCN2019125115-appb-100002
    使用Cu-Kα辐射，所述晶型II的X-射线粉末衍射在衍射角2θ为5.7°±0.2°，8.7°±0.2°，11.5°±0.2°，13.2°±0.2°，17.6°±0.2°，20.1°±0.2°，21.8°±0.2°的位置有特征峰。
  7. 根据权利要求6所述的共晶，其中所述晶型II的X-射线粉末衍射在衍射角2θ为5.7°±0.2°，8.7°±0.2°，11.5°±0.2°，13.2°±0.2°，15.8°±0.2°，16.0°±0.2°，17.6°±0.2°，18.5°±0.2°，20.1°±0.2°，21.8°±0.2°，23.1°±0.2°，25.1°±0.2°的位置有特征峰。
  8. 根据权利要求6所述的共晶，其中所述晶型II的X-射线粉末衍射在衍射角2θ为5.7°±0.2°，8.7°±0.2°，11.5°±0.2°，13.2°±0.2°，15.8°±0.2°，16.0°±0.2°，16.2°±0.2°，16.5°±0.2°，17.6°±0.2°，18.5°±0.2°，20.1°±0.2°，21.8°±0.2°，23.1°±0.2°，25.1°±0.2°，25.8°±0.2°的位置有特征峰。
  9. 如权利要求1或2所述的共晶，其中所述阿哌沙班与马来酸形成式3所示的共晶晶型III：
    Figure PCTCN2019125115-appb-100003
    使用Cu-Kα辐射，所述晶型III的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，6.0°±0.2°，7.2°±0.2°，11.5°±0.2°，15.8°±0.2°，16.1°±0.2°，17.4°±0.2°，21.0°±0.2°的位置有特征峰。
  10. 根据权利要求9所述的共晶，其中所述晶型III的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，6.0°±0.2°，7.2°±0.2°，11.5°±0.2°，11.9°±0.2°，13.3°±0.2°，13.5°±0.2°，15.8°±0.2°，16.1°±0.2°，17.4°±0.2°，19.1°±0.2°，19.9°±0.2°，20.3°±0.2°，21.0°±0.2°的位置有特征峰。
  11. 根据权利要求9所述的共晶，其中所述晶型III的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，6.0°±0.2°，7.2°±0.2°，11.5°±0.2°，11.9°±0.2°，13.3°±0.2°，13.5°±0.2°，15.8°±0.2°，16.1°±0.2°，17.4°±0.2°，19.1°±0.2°，19.9°±0.2°，20.3°±0.2°，21.0°±0.2°，21.9°±0.2°，22.5°±0.2°，24.1°±0.2°的位置有特征峰。
  12. 如权利要求1或2所述的共晶，其中所述阿哌沙班与L-脯氨酸形成式4所示的共晶晶型IV：
    Figure PCTCN2019125115-appb-100004
    使用Cu-Kα辐射，所述晶型IV的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.0°±0.2°，11.9°±0.2°，17.4°±0.2°，19.0°±0.2°，21.0°±0.2°的位置有特征峰。
  13. 根据权利要求12所述的共晶，其中所述晶型IV的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.0°±0.2°，11.0°±0.2°，11.9°±0.2°，13.5°±0.2°，15.5°±0.2°，16.1°±0.2°，17.4°±0.2°，17.8°±0.2°，19.0°±0.2°，21.0°±0.2°的位置有特征峰。
  14. 根据权利要求12所述的共晶，其中所述晶型IV的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，5.7°±0.2°，5.9°±0.2°，7.0°±0.2°，11.0°±0.2°，11.9°±0.2°，13.5°±0.2°，15.5°±0.2°，16.1°±0.2°，17.4°±0.2°，17.8°±0.2°，19.0°±0.2°，21.0°±0.2°，21.5°±0.2°，22.5°±0.2°，24.1°±0.2°的位置有特征峰。
  15. 如权利要求1或2所述的共晶，其中所述阿哌沙班与L-酒石酸形成式5所示的共晶晶型V：
    Figure PCTCN2019125115-appb-100005
    使用Cu-Kα辐射，所述晶型V的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，7.1°±0.2°，8.6°±0.2°，11.0°±0.2°，17.9°±0.2°，19.1°±0.2°，22.7°±0.2°的位置有特征峰。
  16. 根据权利要求15所述的共晶，其中所述晶型V的X-射线粉末衍射在衍射角2θ为5.5°±0.2°，7.1°±0.2°，8.6°±0.2°，11.0°±0.2°，14.3°±0.2°，15.8°±0.2°，16.0°±0.2°，17.9°±0.2°，19.1°±0.2°，20.3°±0.2°，20.5°±0.2°，21.2°±0.2°，21.5°±0.2°，22.7°±0.2°的位置有特征峰。
  17. 根据权利要求15所述的共晶，其中所述晶型V的X-射线粉末衍射在衍射角2θ 为5.5°±0.2°，7.1°±0.2°，8.6°±0.2°，11.0°±0.2°，12.8°±0.2°，14.3°±0.2°，15.8°±0.2°，16.0°±0.2°，17.9°±0.2°，19.1°±0.2°，20.0°±0.2°，20.3°±0.2°，20.5°±0.2°，21.2°±0.2°，21.5°±0.2°，22.7°±0.2°，24.5°±0.2°的位置有特征峰。
  18. 一种如前述权利要求1-17中任一项所述的共晶的制备方法，包括：
    将羧酸与阿哌沙班溶于三氟乙醇与不良溶剂的混合溶剂中，搅拌析晶，过滤，干燥，获得阿哌沙班/羧酸共晶。
  19. 根据权利要求18所述的方法，其中将羧酸与阿哌沙班溶于三氟乙醇与不良溶剂的混合溶剂中，于30-35℃搅拌18小时，而后降温至0-5℃析晶2-10小时，将所得固体过滤，于55℃真空干燥后获得阿哌沙班/羧酸共晶。
  20. 根据权利要求18所述的方法，其中所使用的阿哌沙班与羧酸的摩尔比为1:0.5-1.1，优选1:0.7-1；所使用的阿哌沙班与三氟乙醇的重量体积比为1:5-6；所使用的阿哌沙班与不良溶剂的重量体积比为1:2.5-3.0。
  21. 根据权利要求18所述的方法，其中所使用的不良溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇，优选为甲醇；所使用的羧酸选自丙二酸、D-苹果酸、马来酸、L-脯氨酸或L-酒石酸。
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